The long term success of cardiac transplantation is currently limited by the high incidence of coronary artery disease, a manifestation of chronic rejection. This complication is principally related to antecedent episodes of high grade allograft rejection and/or ongoing alloreactivity. Daclizumab, a humanized anti-CD25 antibody has been added to conventional immunosuppression to block and delete alloreactive T cells which express the high affinity IL-2 receptor alpha, CD25. At low doses this antibody prevents rejection in some but not all patients, suggesting that higher doses may be necessary particularly for poorly matched recipients who are at increased risk of rejection. However, Daclizumab may affect, not only the population of CD25+ alloreactive T helper cells (TH) but also the population of CD25+ regulatory/suppressor T cells which are believed to be crucial to allograft survival. The overall goal of this project is to study the mechanism which determines whether a graft will be rejected or tolerated and to develop a reliable strategy for tailoring the type and amount of immunosuppression to the patient's needs.
The specific aims are: (1) To evaluate the frequency and characteristics of allospecific helper, cytotoxic and regulatory/suppressor T cells in heart allograft recipients treated with conventional immunosuppressive therapy and without (n=53) or with high doses of Daclizumab (n=53). (2) To establish the relationship between T cell alloreactivity, antibody production, acute and chronic rejection (3) To examine whether Daclizumab at 2mg/kg can reduce the frequency of acute and chronic rejection. To meet these objectives we will characterize alloreactive T cells within the graft and periphery with respect to direct or indirect activity and cytokine production. The generation of suppressor and regulatory T cells will be monitored by flow cytometry and functional studies. Anti-HLA class I and II antibodies will be monitored using both lymphocytotoxicity and ELISA methods. Statistical analysis will be performed to determine the relationship between the observed immunological changes and rejection in patients treated with conventional immunosuppressive therapy and with or without high doses (2mg/kg) of Daclizumab.
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